Project Summary Mixed neuropathologies are the most common cause of the clinical syndrome of dementia, including Alzheimer?s disease (AD) dementia, and are also common among persons with mild cognitive impairment, the prodromal stage of AD. Exploiting novel constitutive and conditional knockout lines as well as transgenic mouse lines, we now propose bidirectional genetic effort designed to uncover key knowledge gaps linking alpha-synuclein (?Syn) and tau coupling, and their relationships to synaptic and cognitive function. Leveraging emerging evidence from independent groups including our own, we will test the central hypothesis that ?Syn modulates tau pathology and tau-associated cognitive and synaptic deficits. In the light of novel findings reported in the preliminary results, we will i) test the prediction that constitutive ablation of the SNCA gene encoding ?Syn alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy and ii) test the hypothesis that overexpression of human wild-type ?Syn exacerbates tau pathology and tau-induced cognitive deficits in a model of tauopathy, thereby providing a preclinical proof-of-principle that targeting this ?Syn/tau coupling might be therapeutically beneficial.